Over the past 10 years, we have published a series of articles demonstrating that human NK cells have the potential to contribute to both innate and adaptive immune responses to M. tb. NK cells lyse M. tb-infected alveolar macrophages and produce IL-22, which inhibits intracellular growth of M. tb. NK cells also enhance T-cell responses by lysing M. tb-expanded immunosuppressive CD4+ regulatory T cells (Tregs) and by upregulating CD8+ T-cell responses in persons with LTBI. Our recent unpublished data also show NK cells contribute to T-cell responses to BCG vaccination. Since 2007, we have been collaborating with Dr. Vijaya Valluri at the Blue Peter Research Center, LEPRA Society, Hyderabad, India on studies of NK cells and Tregs. Based on our data and our established collaboration with Dr. Valluri's group, We propose the following aims. 1) Determine if NK cell responses to M. tb are reduced in HIV+ persons with LTBI. We will compare the capacity of NK cells from HIV- and HIV+ persons, with or without LTBI, to mediate innate responses to M. tb and evaluate the capacity of NK cells from HIV- and HIV+ persons, with or without LTBI, to affect T-cell responses 2) Determine if immune-based interventions can enhance NK cell and T-cell function in HIV+ persons with LTBI and active TB. We will devise interventions to improve NK cell function in HIV+ persons with LTBI, determine if interventions to improve NK cell function also enhance T-cell function in HIV+ persons with LTBI and determine if they enhance NK cell and T-cell function in HIV+ persons with active TB. PUBLIC HEALTH RELEVANCE: Mycobacterium tuberculosis infects one-third of the world's population and causes almost 2 million deaths per year. HIV infection markedly increases susceptibility to TB, and HIV-infected persons with latent tuberculosis infection (LTBI) have an 800-fold greater risk of developing active TB. The proposed studies will improve our understanding of the mechanisms that mediate susceptibility to TB in HIV+ persons, and facilitate development of interventions to improve NK cell function and prevent progression of LTBI in HIV-infected persons.